Cytotoxic T lymphocyte - tumor cell interaction: Monitoring HLA class I antigen and HLA class I antigen - tumor antigen derived peptide complex expression by malignant cells
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Poor clinical response rates have been observed in the majority of the T cell-based immunotherapy clinical trials conducted to date. These disappointing results are likely to be caused, at least in part, by tumor cells' ability to evade immune recognition and destruction. In the present thesis, Chapter I summarizes the available information about abnormalities in HLA class I antigen expression in malignant cells, the underlying molecular defects, their potential clinical significance as well as the potential mechanisms underlying the lack of complete correlation between HLA class I antigen expression by malignant cells and susceptibility to HLA class I antigen restricted, TA-specific CTL lysis. Chapter 2 describes the generation of appropriate probes capable of monitoring HLA class I antigen-TA peptide complex expression by malignant cells and addresses the question of whether the assessment of HLA class I antigen expression by tumor cells represents a reliable measure of the actual level of HLA class I antigen-TA derived peptide complexes on the surface of tumor cells. Chapter 3 characterizes the molecular defects underlying HLA class I antigen and HLA class I-TA peptide complex loss found in five melanoma cell lines derived from metastases recurred in patients following initial clinical responses to T cell-based immunotherapy. Chapter 4 provides a detailed assessment regarding the effect of quantitative variations in antigen processing machinery component expression on HLA class I antigen and HLA class I-TA peptide complex expression by malignant cells. Chapters 5 and 6 discuss the frequency of HLA class I antigen abnormalities in surgically removed human melanoma and brain carcinoma lesions, respectively. In the subsequent chapter, a method developed by the author and collaborators for using single chain fragments of antibody variable regions (scFV) in binding assays is presented. Lastly, the final chapter is dedicated to discussing the potential strategies to improve the outcome of T cell-based immunotherapy in patients with malignant disease. They include (i) development of objective criteria to select the most appropriate immunotherapeutic strategy, TA and patient populations; (ii) use of polyvalent vaccines to circumvent tumor immune escape mechanisms; (iii) immune monitoring of tumor antigenic profiles both prior to and during the course of therapy, and (iv) combination of T cell-base immunotherapy with other immunological and non-immunological therapies. (Abstract shortened by UMI.)
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